1-(1,3-Dioxolan-2-ylmethyl)-1H-1,2,4-triazoles

ABSTRACT

Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles and 1H-1,2,4-triazoles useful as antifungal and antibacterial agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 853,728, filed Nov. 21, 1977,now U.S. Pat. No. 4,144,346 issued Mar. 13, 1979, which is acontinuation-in-part of our copending application Ser. No. 764,263,filed Jan. 31, 1977, now abandoned.

BACKGROUND OF THE INVENTION

In U.S. Pat. Nos. 3,575,999, 3,936,470 and Belg. Pat. No. 835,579 thereare described a number of 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles and1H-1,2,4-triazoles having antifungal and antibacterial properties. Thecompounds of this invention differ from the foregoing essentially by thenature of the substituent group in the 4-position of the dioxolanemoiety.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is concerned with novel 1H-imidazole and1H-1,2,4-triazole derivatives which may structurally be represented bythe formula: ##STR1## and the pharmaceutically acceptable acid additionsalt and stereo-chemically isomeric forms thereof, wherein:

Q is a member selected from the group consisting of CH and N;

Ar is a member selected from the group consisting of phenyl andsubstituted phenyl, said substituted phenyl being phenyl having from 1to 3 substituents independently selected from the group consisting ofhalo, lower alkyl and lower alkyloxy;

the radical A is a member selected from the group consisting of:

(a) an isothiocyanato group --N═C═S (a);

(b) an amino radical of the formula ##STR2## wherein R₁ and R₂ are eachindependently selected from the group consisting of hydrogen and loweralkyl;

(c) a radical of the formula ##STR3## wherein X is selected from thegroup consisting of O and S, Y is selected from the group consisting ofO and NH, m is the integer 0 or 1, and R₃ is selected from the groupconsisting of hydrogen, lower alkyl, mono- and dihalo-(lower alkyl),phenyl and substituted phenyl, said substituted phenyl having from 1 to2 substituents independently selected from the group consisting of halo,lower alkyl and lower alkyloxy, provided that:

(i) when said X is S, then said Y is NH and said m is 1, and

(ii) when said Y is O and said m is 1, then said R₃ is other thanhydrogen; and

(d) a radical of the formula ##STR4## wherein Z is a member selectedfrom the group consisting of a direct bond, CH₂, O and N--R₄, wherein R₄is selected from the group consisting of hydrogen, lower alkyl,hydroxy-(lower alkyl), (lower alkyloxy)-lower alkyl, lower alkanoyl,lower alkylsulfonyl, phenylmethylsulfonyl, lower alkyloxycarbonyl, loweralkyloxycarbonylmethyl, phenoxycarbonyl, aminocarbonyl, mono- anddi(lower alkyl)aminocarbonyl, aminocarbonylmethyl, (loweralkyl)aminocarbonylmethyl, (lower alkyl)aminoethioxomethyl, (loweralkylthio)thioxomethyl, phenyl, phenylmethyl, benzoyl and substitutedbenzoyl, said substituted benzoyl being benzoyl having from 1 to 2substituents independently selected from the group consisting of halo,lower alkyl and lower alkyloxy; and R is a member selected from thegroup consisting of hydrogen and nitro, provided that when said R isnitro, then said A is amino.

As used throughout the specification, the term "lower alkyl" denotesstraight and branch chained hydrocarbon radicals having from 1 to 6carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl,1,1'-dimethylethyl, propyl, butyl, pentyl, hexyl and the like; "loweralkanoyl" is meant to include straight and branch chained alkanoylradicals having from 1 to 6 carbon atoms such as, for example, formyl,acetyl, propanoyl, 2-methylpropanoyl, butanoyl, pentanoyl, hexanoyl andthe like; and the term "halo" is generic to halogens of atomic weightless than 127, i.e., fluoro, chloro, bromo and iodo.

Preferred compounds within the scope of formula (I) are those wherein Qstands for CH and R represents hydrogen. Particularly preferredcompounds are those wherein Ar is mono- or dihalophenyl, most preferably2,4-dichlorophenyl.

In order to simplify the structural representation of compounds (I) andof certain starting materials and intermediates used in the preparationthereof, the 2-Ar-2-(1H-imidazol-1-ylmethyl or1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl group, wherein Ar has thepreviously indicated meaning, will hereinafter be represented by thesymbol D: ##STR5##

Compounds of formula (I) wherein A is a radical of the formula (b), aradical of the formula (c) wherein R₃ is other than hydrogen when m is1, or a radical of formula (d) wherein R₄ is other than hydroxy-loweralkyl, said A being represented by A₁ and said compounds by (I-a), canbe prepared by the reaction of an appropriate reactive ester of formula(II) with an appropriately substituted phenol of formula (III). ##STR6##

In formula (II), W is a reactive ester residue such as, for example,halo, methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like.

The reaction of (II) with (III) may be carried out following standardO-alkylating procedures, e.g., by stirring the reactants together atsomewhat elevated temperatures and in the presence of and appropriatebase, in a suitable reaction-inert organic solvent such as, for example,4-methyl-2-pentanone, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide and the like, or mixtures of such solvents with, forexample, aromatic hydrocarbons, e.g. benzene, methylbenzene and thelike. Appropriate bases which may advantageously be employed includealkali and earth alkali metal carbonates, hydrogen carbonates, hydridesand the like, e.g. sodium carbonate, sodium hydrogen carbonate,potassium carbonate, sodium hydride and the like.

When A₁ in (I-a) is an amino radical of formula (b) wherein at least oneof R₁ and R₂ is hydrogen, (I-a-1), or an unsubstituted 1-piperazinylradical, (I-a-2), it is appropriate to use in the foregoing preparationa phenol (III) wherein said amino, respectively piperazinyl, group isprotected with an appropriate protecting group P, (III-a) and (III-b)respectively, in order to avoid N-alkylation, and, to eliminate theprotecting group of the thus obtained (I-a-3) and (I-a-4) by classicalmeans. Appropriate protecting groups include, for example, loweralkanoyl and lower alkyloxycarbonyl groups which may easily be removedby alkaline hydrolysis. ##STR7##

Compounds of formula (I) wherein A stands for an isothiocyanato group,i.e., wherein A has the formula (a), said compounds being represented by(I-b), can easily be derived from a compound (I-a-1) wherein (R₁ or R₂)and R are all hydrogen, (I-a-1'), following art-known methodologies ofpreparing isothiocyanates starting from amines, e.g., by the reaction of(I-a-1') with carbon disulfide in the presence ofN,N'-methanetetraylbis[cyclohexanamine] in pyridine. ##STR8##

Compounds of formula (I) wherein A is an aminothiocarbonylamino radical,i.e., a radical of formula (c) wherein X is S, Y is NH, m is 1 and R₃ ishydrogen, said compounds being represented by (I-c) can be prepared byreacting the corresponding (I-b) with ammonium hydroxide in a suitablesolvent such as, for example, a lower alkanol, e.g. methanol, ethanoland the like. ##STR9##

Compounds of formula (I) wherein A has the formula (c) wherein Y is NHand m is 1, and, wherein X is O when R₃ is hydrogen, (I-d), areconveniently obtained by the reaction of an appropriate amine (I-a-1')with an appropriate isocyanate or isothiocyanate of formula (IV).##STR10##

The foregoing reaction may be carried out according to art-knownmethodologies, e.g., by stirring the reactants together, preferablywhile heating, in an appropriate reaction-inert solvent, e.g.,1,4-dioxane. When R₃ stands for hydrogen, in which case (IV) representshydrocyanic acid, it is appropriate to use an appropriate alkali metalcyanate in aqueous medium, the free acid being liberated by the additionthereto of an appropriate acid, e.g., acetic acid.

Compounds of formula (I) wherein A has the formula (c) wherein X and Yare each O and R₃ and m are as previously defined, (I-e), can beprepared by acylating an appropriate amine (I-a-1') with an appropriateacylating agent according to common N-acylating procedures. Suitableacylating agents which may be used to prepare compounds (I-e) wherein mis zero include acyl halides and anhydrides derived from the acid R₃COOH and also the acid itself, the latter being preferred whenformylation is desired. In order to prepare compounds (I-e) wherein m is1 there may be used appropriate carbonohalidates, preferablycarbonochloridates, and di(R₃)-carbonates. ##STR11##

Compounds of formula (I) wherein A has the formula (d) wherein Z standsfor N-R₄ and said R₄ for an aminocarbonyl, a lower alkylaminocarbonyl ora (lower alkyl)aminothiocarbonyl radical, said compounds beingrepresented by the formula (I-f) wherein R₅ is hydrogen or lower alkyl,may be prepared starting from an appropriate piperazine of formula(I-a-2) by the addition thereto of an appropriate isocyanate orisothiocyanate of formula (V) wherein X is O or S, provided that whensaid R₅ is hydrogen, then said X is O, following similar procedures asdescribed herein for the preparation of compounds (I-d) starting from(I-a-1') and (IV). ##STR12##

Compounds of formula (I) wherein A has the formula (d) wherein Z is N-R₄and said R₄ is selected from the group consisting of lower alkyl,hydroxy(lower alkyl), lower alkyloxycarbonylmethyl, aminocarbonylmethyl,(lower alkyl)aminocarbonylmethyl and phenylmethyl said R₄ beingrepresented by R₄ ' and said compounds by the formula (I-g), can bederived from a compound (I-a-2) by alkylating the latter with anappropriate reactive ester of formula (VI) wherein W and R₄ ' are aspreviously defined, following standard N-alkylating procedures asgenerally known in the art. ##STR13## When R₄ ' in formula (I-g) standsfor a hydroxyethyl radical the same compounds may also be obtained bythe reaction of (I-a-2) with oxirane e.g. by bubbling the latter througha heated solution of (I-a-2) in a suitable organic solvent such as alower alkanol, e.g. methanol, ethanol or 2-propanol.

When R₄ ' in formula (I-g) represents a primary or secondary lower alkylgroup or a phenylmethyl group said compounds may also be prepared from(I-a-2) and an appropriate aldehyde or ketone according to a reductiveamination reaction, for example, by hydrogenating a mixture of thereactants in an appropriate reaction-inert organic solvent such as alower alkanol, e.g., methanol or ethanol, in the presence of anappropriate catalyst such as, for example, palladium-on-charcoal, and anappropriate base such as sodium acetate.

Compounds of formula (I-g) wherein R₄ ' represents a (loweralkyl)-aminocarbonylmethyl radical may also be derived from thecorresponding compounds (I-g) wherein R₄ ' is loweralkyloxycarbonylmethyl by the reaction of the latter with an appropriatelower alkanamine following art-known procedures of preparing amidesstarting from esters.

Compounds of formula (I) wherein A has the formula (d) wherein Z is NR₄and said R₄ is an acyl radical selected from the group consisting oflower alkanoyl, lower alkylsulfonyl, phenylmethylsulfonyl, loweralkyloxycarbonyl, phenoxycarbonyl, aminocarbonyl, mono- and di(loweralkyl)aminocarbonyl, benzoyl and substituted benzoyl, said R₄ beingrepresented by R₄ " and said compounds by the formula (I-h), canconveniently be obtained by acylating an appropriate compound (I-a-2)with an appropriate acylating agent following standard N-acylatingprocedures. In general said acylation may be performed by the reactionof (I-a-2) with an appropriate acyl halide, derived from thecorresponding carboxylic or sulfonic acid, or, when the acyl group to beintroduced is lower alkanoyl, benzoyl or substituted benzoyl by thereaction with an anhydride of the corresponding acid or with the aciditself, the latter being preferred when formylation is desired. When theacyl group to be introduced is lower alkyloxycarbonyl or phenoxycarbonylthere may also be used an appropriate di(lower alkyl)- or diphenylcarbonate as an acylating agent. ##STR14## Compounds of formula (I-h)wherein R₄ " stands for lower alkanoyl may if desired be reduced with anappropriate reducing agent such as, for example, lithium aluminiumhydride to obtain a corresponding compound of formula (I-g) wherein R₄ 'is a lower alkyl group which is unbranched at the α-carbon atom.

Compounds of formula (I) wherein A has the formula (d) wherein Z standsfor N-R₄ and said R₄ is a (lower alkylthio)thioxomethyl group, (I-i),can be derived from (I-a-2) by reacting the latter with carbon disulfideand an appropriate alkylating agent to introduce the lower alkyl group,e.g. a di(lower alkyl) sulfate, in an appropriate solvent such as, forexample, a mixture of a lower alkanol, e.g., methanol, and water.##STR15##

Compounds of formula (I) wherein A has the formula (d) wherein Z standsfor N-R₄ and said R₄ is (lower alkyloxy)lower alkyl are easily derivedfrom the corresponding hydroxy(lower alkyl)substituted compounds byalkylating the latter according to art-known O-alkylating procedures aspreviously described herein for the preparation of the compounds (I-a)starting from (II) and (III).

Compounds of the formulae (I-a-1') and (I-b) as well as compounds offormula (I-e) wherein R₃ is phenyl and m is 1, and compounds of formula(I-e) wherein m is zero and R₃ is lower alkyl are also described in ourapplication Ser. No. 764,265, filed Jan. 31, 1977, and subsequentlyfiled as a continuation-in-part application on even date with thisapplication.

Starting materials of formula (II) wherein Q stands for CH and methodsof preparing the same are described in Belg. Pat. No. 837,831. Ingeneral the reactive esters of formula (II) can be prepared along thefollowing sequence of reactions.

An appropriate 1-Ar-2-bromoethanone of formula (VII) is subjected to aketalization reaction with 1,2,3-propanetriol following methodologiesanalogous to those described in Synthesis, 1974 (I), 23.

In a preferred manner of carrying out the reaction both reactants arerefluxed together for several hours with azeotropic water removal in anappropriate organic solvent, preferably in the presence of a simplealcohol, such as, for example, ethanol, propanol, butanol, pentanol andthe like, and in the presence of an appropriate strong acid such as4-methylbenzenesulfonic acid. Suitable organic solvents are, forexample, aromatic hydrocarbons, such as benzene, methylbenzene,dimethylbenzene and the like and saturated hydrocarbons, such ascyclohexane.

The thus obtained dioxolane (VIII) is then reacted with benzoyl chlorideto obtain a benzoate of the formula (IX) and the latter is subsequentlyreacted with 1H-imidazole or 1H-1,2,4-triazole. Said reaction ispreferably carried out by stirring and heating the reactants together ina suitable organic solvent, e.g. N,N-dimethylformamide, in the presenceof an appropriate strong metal base, e.g. sodium methanolate to obtainan intermediate of the formula (X). The desired reactive esters offormula (II) are then conveniently prepared by first hydrolyzing (X) inalkaline medium and thereafter converting the hydroxy group of the thusobtained (XI) into a reactive ester thereof according to methodologiesgenerally known in the art. For example, methanesulfonates and4-methylbenzenesulfonates are conveniently prepared by the reaction ofthe alcohol with methanesulfonyl chloride or 4-methylbenzenesulfonylchloride and halides may be prepared by the reaction of the alcohol withan appropriate halogenating agent such as, for example, sulfurylchloride, phosphor pentachloride, phosphor pentabromide, phosphorylchloride and the like. When the reactive ester is an iodide, it ispreferably prepared from the corresponding chloride or bromide by thereplacement of that halogen with iodine.

The foregoing reactions may be illustrated as follows: ##STR16##

An important number of the starting materials of formula (III) are alsoknown compounds and the remaining may generally be derived fromaminophenols and (1-piperazinyl)phenols following art-known proceduresas previously described herein for the preparation of the requiredA-groups in compounds (I) starting from (I-a-1) and (I-a-2). When thephenolic hydroxyl group would interfere with such synthetic proceduresit is appropriate to first protect said group with an appropriateprotecting group, the latter being removed at a later stage. Forexample, the protected phenol may take the form of a methoxy-compound,the methoxy group of which is ultimately transformed into the desiredhydroxy group by the treatment of the former with an appropriate strongacid, e.g., hydrobromic acid, or there may be used an acyloxy compound,and acyl group of which can be removed by alkaline hydrolysis.

The compounds of formula (I) have basic properties and thus may beconverted to their therapeutically useful acid addition salts byreaction with an appropriate acid, as, for example, an inorganic acidsuch as hydrohalic acid, i.e., hydrochloric, hydrobromic or hydroiodicacid; sulfuric, nitric or thiocyanic acid; a phosphoric acid; andorganic acid such as acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic,1,4-butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxy-1,4-butanedioic, 2,3-dihydroxy-1,4-butanedioic,2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic,α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, 4-methylbenzenesulfonic, 2-hydroxybenzoic,4-amino-2-hyroxybenzoic, 2-phenoxybenzoic or 2-acetyloxybenzoic acid.The salts are in turn converted to the corresponding free bases in theusual manner, e.g. by reaction with alkali such as sodium or potassiumhydroxide.

From formula (I) it is evident that the compounds of this invention haveat least two asymmetric carbon atoms in their structures, namely thoselocated in the 2- and 4-positions of the dioxolane nucleus, andconsequently they can exist under different stereochemically isomericforms. The stereochemically isomeric forms of (I) and thepharmaceutically acceptable acid addition salts thereof are intended tobe within the scope of this invention.

The diastereomeric racemates of (I), denoted as cis and trans formsrespectively, according to the rules described in C.A., 76, Index Guide,Section IV, p. 85 (1972), may be obtained separately by conventionalmethods. Appropriate methods which may advantageously be employedtherefore include, for example, selective crystallization andchromatography separation, e.g. column chromatography.

Since the stereochemical configuration is already fixed in theintermediates (II) it is also possible to separate cis and trans formsat this or even an earlier stage, whereupon the corresponding forms of(I) may be derived therefrom in the previously indicated manner. Theseparation of cis and trans forms of such intermediates may be performedby conventional methods as described hereabove for the separation of cisand trans forms of the compounds (I).

It is evident that the cis and trans diastereomeric racemates may befurther resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of methodologies known to those skilledin the art.

The compounds of formula (I) and the pharmaceutically acceptable acidaddition salts thereof are useful agents in combatting fungi andbacteria. For example, said compounds and acid addition salts thereofwere found to be highly active against a wide variety of fungi such as,for example, Microsporum canis, Ctenomyces mentagrophytes, Trichophytonrubrum, Phialophora verrucosa, Cryptococcus neoformans, Candidatropicalis, Candida albicans, Mucor species, Aspergillus fumigatus,Sporotrichum schenckii and Saprolegnia species, and against bacteriasuch as, for example, Erysipelotrix insidiosa, Staphylococci such asStaphylococcus hemolyticus and Streptococci such as Streptococcuspyogenes. In view of their potent, local as well as systemic,antimicrobial activity the compounds of this invention constitute usefultools for the destruction or prevention of the growth of fungi andbacteria and more particularly they can effectively be used in thetreatment of subjects suffering from such microorganism.

The strong antimicrobial activity of the compounds (I) is clearlyevidenced by the data obtained in the following experiments, which datais only given to illustrate the useful antimicrobial properties of allthe compounds (I) and not to limit the invention either with respect tothe scope of susceptible microorganisms nor with respect to the scope offormula (I).

Experiment A: Activity of Compounds (I) Against Vaginal Candidosis inRats

Female Wistar rats of ±100 g body weight were used. They wereovariectomized and hysterectomized and after three weeks of recovery,100 μg of oestradiol undecylate in sesame oil was given subcutaneouslyonce a week for 3 consecutive weeks. The thus induced pseudooestrus wascontrolled by microscopic examination of vaginal smears. Food and waterwere left available ad libitum.

The rats were infected intravaginally with 8.10⁵ cells of Candidaalbicans, grown on Sabouraud broth for 48 hours at 37° C. and dilutedwith saline. The date of infection varied from day +25 to day +32 aftersurgical intervention, depending on the appearance of signs of inducedpseudo-oestrus.

The drugs under investigation were administered orally once a day fortwo days starting from the day of infection. For each experiment therewere placebo treated controls. The results were assessed by takingvaginal smears with sterile swabs on several days after infection. Theswabs were put into Sabouraud broth in petri-dishes and incubated for 48hours a 37° C. If no growth of Candida albicans occured, i.e., when theanimals were negative at the end of the experiment, this was due to drugadministration because it never happened in placebo treated controls.

The Tables I, II and III below give the lowest oral dose of the drugunder investigation which was found active at the 14th day afterinfection.

Experiment B: Activity of Compounds (I) Against Crop Candidosis inTurkeys

Turkeys of 14 days old were infected in the crop with 4.10⁶ Candidaalbicans cells, grown on Sabouraud broth for 48 hours at 37° C. anddiluted with saline. The volume of the inoculum was 1 ml. The drug underinvestigation were premixed in 500 mg of lacton and thereafter admixedin 1000 g of meal without any additives. The concentration of the drugunder investigation in the meal was expressed in mg/kg.

The animals were given the medicated feed for 13 consecutive daysstarting on the day of infection. At the end of the experiment allanimals were sacrificed. At autopsy the crops were removed, emptied andgrinded in an ultra-turrax mixer in 15 ml of sterile saline. Colonycounting was done on Sabouraud agar and the results given in the TablesI, II and III represent the ED₅₀, i.e., the dose of the drug whereby thecrops of 50% of the animals were completely negative for Candidaalbicans.

                                      TABLE I                                     __________________________________________________________________________     ##STR17##                                                                                                    Vaginal candidosis in rats:                                                                     Crop candidosis in                                                            turkeys                       A                  Base or Salt                                                                             lowest effective oral dose in                                                                   ED.sub.50 in mg/kg of                                                         feed                        __________________________________________________________________________    NCS                  base       5                 125                         NH.sub.2             base       5                 125                          ##STR18##           2(COOH).sub.2 H.sub.2 O                                                                  10                31                          NHCHO                base       2.5               31                          NHCOCH.sub.3         base       5                 31                          NHCOC.sub.2 H.sub.5  (COOH).sub.2                                                                             10                31                                               (CH.sub.3).sub.2CHOH                                     NHCOCH(Cl).sub.2     base       10                125                          ##STR19##           base       5                 63                           ##STR20##           base       5                 16                           ##STR21##           base       --                31                           ##STR22##           base       10                31                           ##STR23##           base       40                16                          NHCOOCH.sub.3        HNO.sub.3  5                 31                          NHCOOC.sub.2 H.sub.5 base       5                 16                           ##STR24##           base       10                125                         NHCONHCH.sub.3       base       10                125                         NHCONHC.sub.2 H.sub.5                                                                              base       10                125                         NHCSNH.sub.2         base       20                --                          NHCSNHCH.sub.3       base       10                125                         NHCSNHC.sub.2 H.sub.5                                                                              base       5                 125                          ##STR25##           base       --                16                           ##STR26##           base       2.5               16                           ##STR27##           base       5                 125                          ##STR28##           base       <10               --                           ##STR29##           base       2.5                8                           ##STR30##           base       2.5                8                           ##STR31##           base       2.5               16                           ##STR32##           base       5                 125                          ##STR33##           base . H.sub.2 O                                                                         2.5               16                           ##STR34##           base . H.sub.2 O                                                                         10                125                          ##STR35##           base . 2H.sub.2 O                                                                        2.5               125                          ##STR36##           base . H.sub.2 O                                                                         2.5               125                          ##STR37##           2(COOH).sub.2                                                                            1.25              31                           ##STR38##           2HCl       2.5                8                           ##STR39##           2HCl . 1/2H.sub.2 O                                                                      10                31                           ##STR40##           2(COOH).sub.2 . C.sub.2 H.sub.5 OH                                                       2.5               --                           ##STR41##           3HCl . H.sub.2 O                                                                         --                16                           ##STR42##           3HCl . CH.sub.3CHOHCH.sub.3                                                              2.5               --                           ##STR43##           3HCl . H.sub.2 O                                                                         --                31                           ##STR44##           base . 21/2 (COOH).sub.2                                                                 2.5               16                          NHCH.sub.2CH.sub.3   base       2.5               31                          NHCH.sub.3           base       5                 --                           ##STR45##           base . H.sub.2 O                                                                         1.25              31                           ##STR46##           3HCl . H.sub.2 O                                                                         2.5               31                           ##STR47##           base       --                16                           ##STR48##           base       1.25              --                           ##STR49##           base       <2.5              --                           ##STR50##           base       1.25              16                          __________________________________________________________________________

                  Table II                                                        ______________________________________                                         ##STR51##                                                                                             Vaginal                                                                       candidosis                                                                              Crop                                                                in rate:  candidosis                                                          lowest    in turkeys:                                                         effective ED.sub.50                                                Base or Salt                                                                             oral dose in                                                                            in mg/kg                                   R.sub.4       form       mg/kg     of feed                                    ______________________________________                                        (CH.sub.2).sub.3CH.sub.3                                                                    base       --        16                                         CH(CH.sub.3)CH.sub.2CH.sub.3                                                                base       2.5       63                                         COC.sub.2 H.sub.5                                                                           2 HCl      --        8                                          COOC.sub.2 H.sub.5                                                                          2 HCl      --        8                                          CHO           base       1.25      16                                         CO(CH.sub.2).sub.2CH.sub.3                                                                  2 HCl      --        16                                         CH.sub.2CH(CH.sub.3).sub.2                                                                  base       2.5       31                                         CH(CH.sub.3).sub.2                                                                          base       2.5       --                                         COOCH.sub. 3  base       --        8                                          SO.sub.2CH.sub.2C.sub.6 H.sub.5                                                             base . H.sub.2 O                                                                         --        16                                         COOC.sub.6 H.sub.5                                                                          base       --        16                                         (CH.sub.2).sub.2CH.sub.3                                                                    base       --        16                                         COCH.sub.3    base       1.25      8                                          CH.sub.3      base       1.25      16                                         SO.sub.2CH.sub.3                                                                            base . 1.2H.sub. 2 O                                                                     1.25      31                                         COC.sub.6 H.sub.5                                                                           base       1.25      --                                         ______________________________________                                    

                                      Table III                                   __________________________________________________________________________    Compounds of formula (I).                                                                                                   Vaginal                                                                       candidosis                                                                             Crop candidosis                                                      in rats: lowest                                                                        in turkeys                                             Iso-                                                                             Base or Salt                                                                             effective oral                                                                         ED.sub.50 mg/kg        Q  Ar        A              R   mer                                                                              form       in mg/kg.                                                                              of                     __________________________________________________________________________                                                           feed                   CH 4-OCH.sub.3C.sub.6 H.sub.4                                                             ##STR52##       H   -- 1/2(E)- HOOCCHCH COOH                                                                    2.5      --                     CH 4-OCH.sub.3C.sub.6 H.sub.4                                                             ##STR53##       H   -- base       --       31                     CH 2,4-Cl.sub.2C.sub.6 H.sub.3                                                           3 (NHCOCH.sub.3) H   cis                                                                              HNO.sub.3  10       63                     CH 2,4-Cl 2C.sub.6 H.sub.3                                                                ##STR54##       H   cis                                                                              base       2.5      --                     CH 2,4-Cl.sub.2C.sub.6 H.sub.3                                                           4-NH.sub.2       3-NO.sub.2                                                                        cis                                                                              base       5.0      31                     __________________________________________________________________________

In view of their antifungal and antibacterial properties this inventionprovides valuable compositions comprising the subject compounds offormula (I) or acid addition salts thereof as the active ingredient in asolvent or a solid, semi-solid or liquid diluent or carrier, and, inaddition, it provides an effective method of combatting fungal orbacterial growth by use of an effective antifungal or antibacterialamount of such compounds (I) or salts thereof. Antifungal andantibacterial compositions comprising an effective amount of an activecompound (I), either alone or in combination with other activetherapeutic ingredients, in admixture with suitable carriers may bereadily prepared according to conventional pharmaceutical techniques forthe usual routes of administration.

Preferred compositions are in dosage unit form, comprising per dosageunit an effective quantity of the active ingredient in admixture withsuitable carriers. Although the amount of the active ingredient per unitdosage may vary within rather wide limits, dosage units comprising fromabout 50 to about 500 mg and more particularly from about 100 to about250 mg of the active ingredient are preferred.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Unless otherwise stated all parts therein are by weight.

EXAMPLE I

A mixture of 2.4 parts of N-(4-hydroxyphenyl)-benzamide, 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate, 2 parts of potassium carbonate and 75 parts ofdimethylsulfoxide is stirred overnight at 100° C. The reaction mixtureis cooled and poured onto water. The product is extracted twice withtrichloromethane. The combined extracts are washed twice with water,dried, filtered and evaporated. The residue is crystallized from1-butanol. The product is filtered off and dried, yielding 2.7 parts(51%) ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}benzamide;mp. 217.6° C.

EXAMPLE II

Following the procedure of Example I and using therein an equivalentamount of an appropriate substituted N-(4-hydroxyphenyl)benzamide as astarting material the following compounds are prepared:

cis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-methoxybenzamide;mp. 188.7° C.;

cis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-fluorobenzamide;mp. 198.2° C.;

cis-ethyl{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}carbamate;mp. 178.9° C.; and

cis-4-bromo-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}benzamide;mp. 217.9° C.

EXAMPLE III

A mixture of 2.8 parts of 4-chloro-N-(4-hydroxyphenyl)benzamide, 0.4parts of sodium hydride dispersion 78%, 75 parts of dimethylsulfoxideand 18 parts of benzene is stirred for one hour at 40° C. Then there areadded 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethylmethanesulfonate and the whole is stirred overnight at 100° C. Thereaction mixture is cooled and poured onto water. The product isextracted twice with benzene. The combined extracts are washed withwater, dried, filtered and evaporated. The residue is crystallized from1-butanol. The product is filtered off and dried, yielding 3.2 parts(58%) ofcis-4-chloro-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}benzamide;mp. 213.3° C.

EXAMPLE IV

A mixture of 1.8 parts of 4-(1-pyrrolidinyl)-phenol, 0.4 parts of sodiumhydride dispersion 78% and 100 parts of dimethylsulfoxide is stirred forone hour at 40° C. Then there are added 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate and stirring is continued overnight at 100° C. Thereaction mixture is cooled and poured onto water. The product isextracted with 1,1'-oxybisethane. The extract is washed twice withwater, dried, filtered and evaporated. The residue is crystallized from1,1'-oxybisbutane. The product is filtered off and dried, yielding 2.3parts (48%) ofcis-1-{2-(2,4-dichlorophenyl)-4-[4-(1-pyrrolidinyl)phenoxymethyl]-1,3-dioxolan-2-yl-methyl}-1H-imidazole;mp. 149.1° C.

EXAMPLE V

A mixture of 1.9 parts of 4-(4-morpholinyl)-phenol, 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate, 2 parts of potassium carbonate and 80 parts of4-methyl-2-pentanone is stirred and refluxed overnight. The reactionmixture is cooled, water is added and the product is extracted twicewith 1,1'-oxybisethane. The combined extracts are dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using trichloromethane as eluent. The pure fractions are collectedand the eluent is evaporated. The residue is crystallized from1,1'-oxybisbutane, yielding, after drying, 2.3 parts (47%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}morpholine;mp. 135° C.

EXAMPLE VI

A mixture of 1.9 parts of 4-(dimethylamino)-phenol hydrochloride, 4.2parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate, 4 parts of potassium carbonate and 80 parts of4-methyl-2-pentanone is stirred and refluxed overnight. The reactionmixture is cooled, water is added and the product is extracted twicewith 1,1'-oxybisethane. The combined extracts are washed with water,dried, filtered and evaporated. The residue is converted into theethanedioate salt in 2-propanone and 2,2'-oxybispropane. The salt isfiltered off and crystallized from ethanol, yielding 2.4 parts (37%) ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-N,N'-dimethylbenzenaminediethanedioate.hydrate; mp. 112.5° C.

EXAMPLE VII

A mixture of 1.8 parts of N-(4-hydroxyphenyl)-propanamide, 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate, 2 parts of potassium carbonate and 67.5 parts ofN,N-dimethylformamide is stirred and heated overnight at 100° C. Thereaction mixture is cooled and poured onto water. The product isextracted twice with benzene. The combined extracts are washed withwater, dried, filtered and evaporated. The residue is converted into theethanedioate salt in 4-methyl-2-pentanone and 2,2'-oxybispropane. Thesalt is filtered off and crystallized from 2-propanol. The product isfiltered off and dried over week-end at 80° C., yielding 2.3 parts (37%)ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}propanaideethanedioate. 2-propanolate; mp. 116.9° C.

EXAMPLE VIII

A mixture of 1.7 parts of N-(4-hydroxyphenyl)-acetamide, 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate, 2 parts of potassium carbonate and 68 parts ofN,N-dimethylformamide is stirred overnight at 100° C. The reactionmixture is cooled and poured onto water. The product is extracted twicewith trichloromethane. The combined extracts are washed twice withwater, dried, filtered and evaporated. The residue is triturated in amixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product isfiltered off and crystallized from 4-methyl-2-pentanone, yielding 2.8parts (61%) ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamide;mp. 180.5° C.

A mixture of 8.9 parts ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-1-ylmethoxy]phenyl}acetamide,1.5 parts of potassium hydroxide and 80 parts of 1-butanol is stirredand refluxed overnight. The reaction mixture is evaporated and water isadded to the residue. The precipitated product is filtered off andcrystallized from methylbenzene, yielding 6.6 parts (82%) ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;mp. 164.4° C.

EXAMPLE IX

A mixture of 0.8 parts of isothiocyanatomethane, 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine,and 100 parts of 1,4-dioxane is stirred and refluxed for 3 hours. Thesolvent is evaporated and the residue is crystallized from4-methyl-2-pentanone. The product is filtered off and recrystallizedfrom acetonitrile, yielding 2.7 parts (53%) ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidzol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-N'-methylthiourea;mp. 130.7° C.

EXAMPLE X

Following the procedure of Example IX and using an equivalent amount ofisothiocyanatoethane in place of the isothiocyanatomethane used therein,there is prepared:

cis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N'-ethylthiourea;mp. 140.4° C.

EXAMPLE XI

To a stirred solution of 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenaminein 10 parts of acetic acid are added 20 parts of water. Then there isadded a solution of 1 part of potassium isocyanate in 20 parts of waterand the whole is stirred for one hour at room temperature. After theaddition of 200 parts of water, the mixture is neutralized withpotassium carbonate. The product is extracted with trichloromethane. Theextract is dried, filtered and evaporated. The residue is crystallizedfrom 4-methyl-2-pentanone. The product is filtered off andrecrystallized from 4-methyl-2-pentanone, yielding 2.9 parts (62%) odcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-urea;mp. 155.1° C.

EXAMPLE XII

A mixture of 1 part of isocyanatomethane, 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamineand 75 parts of 1,4-dioxane is stirred overnight at room temperature.The reaction mixture is evaporated and the residue is crystallized from4-methyl-2-pentanone. The product is filtered off and dried, yielding3.5 parts (73%) ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N'-methylurea;mp. 169° C.

EXAMPLE XIII

Following the procedure of Example XII and using an equivalent amount ofrespectively isocyanatoethane and isocyanatobenzene in place of theisocyanatomethane used therein, there are prepared respectively:

cis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N'-ethylurea;mp. 154.3° C.; and

cis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N'-phenylureanitrate; mp. 127.3° C.

EXAMPLE XIV

A mixture of 40 parts of formic acid and 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzamineis stirred and refluxed for 48 hours. The reaction mixture is cooled andevaporated. The residue is dissolved in water and neutralized withsodium hydrogen carbonate. The product is extracted twice withtrichloromethane. The combined extracts are dried, filtered andevaporated. The residue is crystallized from a mixture of4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 3.8 parts (85%) ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}formamide;mp. 132.6° C.

EXAMPLE XV

A mixture of 1.8 parts of methyl carbonochloridate, 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine,2 parts of potassium carbonate and 75 parts of 1,4-dioxane is stirredand refluxed for one hour. The reaction mixture is cooled and pouredonto water. Upon the addition of 2,2'-oxybispropane, the product isprecipitated. It is filtered off and converted into the nitrate salt in2-propanone and 2,2'-oxybispropane. The salt is filtered off andcrystallized from acetonitrile, yielding 3.4 parts (63%) of cis-methyl{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl-1,3-dioxolan-4-ylmethoxy]phenyl}-carbamatenitrate; mp. 157.6° C.

EXAMPLE XVI

A mixture of 1.7 parts of dichloroacetyl chloride, 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenamine,2 parts of potassium carbonate and 100 parts of 1,4-dioxane is stirredand refluxed for 4 hours. The reaction mixture is cooled and poured ontowater. The product is extracted twice with 1,1'-oxybisethane. Thecombined extracts are dried, filtered and evaporated. The residue iscrystallized from 4-methyl-2-pentanone. The product is filtered off anddried, yielding 3.9 parts (73%) ofcis-2,2-dichloro-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamide;mp. 165.6° C.

EXAMPLE XVII

To a stirred and cooled (ice-bath) solution of 8.4 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenaminein 75 parts of pyridine and 112 parts of trichloromethane are addeddropwise 3.5 parts of phenyl carbonchloridate. Upon completion, stirringis continued for 3 hours at room temperature. The reaction mixture ispoured onto water and the product is extracted twice withtrichloromethane. The combined extracts are dried, filtered andevaporated. The residue is triturated in a mixture of 1,1'-oxybisethaneand 2,2'-oxybispropane. The product is filtered off and crystallizedfrom 4-methyl-2-pentanone, yielding 8.6 parts of cis phenyl{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}carbamate; mp. 170.6° C.

EXAMPLE XVIII

To a stirred and cooled (ice-salt bath) solution of 13 parts of carbondisulfide and 2.1 parts of N,N'-methanetetraylbis[cyclohexanamine] in 15parts of pyridine is added dropwise a solution of 4.2 parts ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]benzenaminein 25 parts of pyridine at a temperature between -10° C. and -5° C. Uponcompletion, stirring is continued first at -10°--5° C. for 3 hours andfurther at room temperature for one hour. The reaction mixture isevaporated. The residue is dissolved in 20 parts of acetic acid. Thesolution is stirred and 50 parts of water are added. The formedprecipitate is filtered off and the filtrate is neutralized withpotassium carbonate. The product is extracted with 1,1'-poxybisethane.The extract is dried, filtered and evaporated. The residue is purifiedby column-chromatography over silica gel using trichloromethane aseluent. The pure fractions are collected and the eluent is evaporated.The residue is crystallized from a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane. The product is filtered off and dried, yielding 3.2parts (69%) ofcis-1-[2-(2,4-dichlorophenyl)-4-(4-isothiocyanatophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazole;mp. 136° C.

EXAMPLE XIX

A mixture of 90 parts of ammonium hydroxide, 5 parts ofcis-1-[2-(2,4-dichlorophenyl)-4-(4-isothiocyanatophenoxymethyl)-1,3-dioxolan-2-ylmethyl]-1H-imidazoleand 200 parts of methanol is stirred for 3 hours at room temperature.The reaction mixture is poured onto water and the product is extractedwith trichloromethane. The extract is washed with water, dried, filteredand evaporated. The residue is purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (98:2 byvolume) as eluent. The pure fractions are collected and the eluent isevaporated. The residue is crystallized from 4-methyl-2-pentanone,yielding 2.8 parts (54%) ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}thiourea;mp. 190.4° C.

EXAMPLE XX

A. A mixture of 33.8 parts of 4-(1-piperazinyl)-phenol dihydrobromide,11.2 parts of acetic acid anhydride, 42 parts of potassium carbonate and300 parts of 1,4-dioxane is stirred and refluxed for 3 days. Thereaction mixture is filtered and the filtrate is evaporated. The solidresidue is stirred in water and sodium hydrogen carbonate is added. Thewhole is stirred for 30 minutes. The precipitated product is filteredoff and dissolved in a diluted hydrochloric acid solution. The solutionis extracted with trichloromethane. The acid aqueous phase is separatedand neutralized with ammonium hydroxide. The product is filtered off andcrystallized from ethanol, yielding 5.7 parts of1-acetyl-4-(4-hydroxyphenyl)piperazine; mp. 181.3° C.

B. A mixture of 2.4 parts of 1-acetyl-4-(4-hydroxyphenyl)piperazine, 0.4parts of sodium hydride dispersion 78%, 75 parts of dimethylsulfoxideand 22.5 parts of benzene is stirred for one hour at 40° C. Then thereare added 4.2 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate and stirring is continued overnight at 100° C. Thereaction mixture is cooled and diluted with water. The product isextracted with 1,1'-oxybisethane. The extract is dried, filtered andevaporated. The residue is crystallized from 4-methyl-2-pentanone. Theproduct is filtered off and dried, yielding 3.2 parts (59%) ofcis-1-acetyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;mp. 146° C.

EXAMPLE XXI

A mixture of 21 parts ofcis-1-acetyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,10 parts of potassium hydroxide and 200 parts of 1-butanol is stirredand refluxed overnight. The reaction mixture is cooled and benzene isadded. The wole is washed with water, dried, filtered and evaporated.The residue is crystallized from 4-methyl-2-pentanone. The product isfiltered off and dried, yielding 13.9 parts (71%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazine;mp. 170.7° C.

EXAMPLE XXII

A mixture of 0.9 parts of isothiocyanatomethane, 4.9 parts ofcis-1{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazineand 100 parts of 1,4-dioxane is stirred overnight at room temperature.The precipitated product is filtered off and crystallized from1,4-dioxane. It is filtered off again and recrystallized from4-methyl-2-pentanone, yielding 2.7 parts (47%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-methyl-1-piperazinecarbothioamidemonohydrate; mp. 138.2° C.

EXAMPLE XXIII

A mixture of 1 part of isothiocyanatoethane, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazineand 130 parts of dichloromethane is stirred for 3 hours at roomtemperature. The reaction mixture is evaporated and the residue istriturated in a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane.The product is filtered off and crystallized from 4-methyl-2-pentanone,yielding 5.2 parts (89%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-ethyl-1-piperazinecarbothioamide.hemihydrate;mp. 187.9° C.

EXAMPLE XXIV

A mixture of 0.7 parts of isocyanatomethane, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazineand 100 parts of 1,4-dioxane is stirred overnight at room temperature.The solvent is evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 4-methyl-2-pentanone. The product is filtered off anddried, yielding 3.7 parts (66%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-methyl-1-piperazinecarboxamidemonohydrate; mp. 120.6° C.

EXAMPLE XXV

Following the procedure of Example XXIV and using equivalent amounts ofrespectively isocyanatoethane and isocyanatopropane in place of theisocyanatomethane used therein, the following compounds are respectivelyobtained;

cis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-ethyl-1-piperazinecarboxamidemonohydrate; mp. 121.2° C.; and

cis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-propyl-1-piperazinecarboxamidedihydrate; mp. 111.1° C.

EXAMPLE XXVI

A mixture of 1 part of potassium isocyanate, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazine,0.6 parts of acetic acid, 50 parts of water and 50 parts of 1,4-dioxaneis stirred overnight at room temperature. The solvent is evaporated andthe residue is purified by column-chromatography over silica gel using amixture of trichloromethane and methanol (98:2 by volume) as eluent. Thepure fractions are collected and the eluent is evaporated. The residueis crystallized from 4-methyl-2-pentanone. The product is filtered offand dried, yielding 2 parts (38%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl-methoxy]phenyl}-1-piperazinecarboxamide;mp. 189.8° C.

EXAMPLE XXVII

A mixture of 1.2 parts of methyl carbonochloridate, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,2 parts of sodium hydrogen carbonate, 100 parts of 1,4-dioxane and 50parts of water is stirred overnight at room temperature. Water is addedto the reaction mixture. The precipitated product is filtered off andcrystallized from 4-methyl-2-pentanone, yielding 3.8 parts (69%) ofcis-methyl4-}4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl-methoxy[phenyl}-1-piperazinecarboxylate;mp. 137.5° C.

EXAMPLE XXVIII

Following the procedure of Example XXVII there is prepared cis-ethyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxylate;mp. 112.2° C. by the reaction of ethyl carbonochloridate withcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl-methoxy]-phenyl}piperazine.

EXAMPLE XXIX

A mixture of 60 parts of formic acid and 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazineis stirred and refluxed overnight. The reaction mixture is cooled, wateris added and the whole is alkalized with a sodium hydroxide solution50%. The product is extracted with trichloromethane. The extract isdried, filtered and evaporated. The residue is crystallized from4-methyl-2-pentanone, yielding 5.3 parts (100%) ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxaldehyde;mp. 153.4° C.

EXAMPLE XXX

A mixture of 2 parts of dimethylcarbamic chloride, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazine,4 parts of potassium carbonate, 130 parts of dichloromethane and 20parts of water is stirred for 3 hours at room temperature. The reactionmixture is diluted with water and the whole is stirred overnight at roomtemperature. The dichloromethane-phase is separated and the solvent isevaporated. The residue is triturated in a mixture of4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered offand recrystallized from 4-methyl-2-pentanone, yielding 4.8 parts (86%)ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N,N-dimethyl-1-piperazinecarboxamide;mp. 143.8° C.

EXAMPLE XXXI

A mixture of 1.5 parts of benzoyl chloride, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]piperazine,3 parts of potassium carbonate, 130 parts of dichloromethane and 20parts of water is stirred for one hour at room temperature. Water isadded and the whole is stirred for 2 hours at room temperature. Theorganic phase is separated, dried, filtered and evaporated. The residueis converted into the ethanedioate salt in 2-propanone. The salt isfiltered off and crystallized from a mixture of ethanol and2,2'-oxybispropane, yielding 5.9 parts (80%) ofcis-1-benzoyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazineethanedioate (2:3) hemihydrate; mp. 132.9° C.

EXAMPLE XXXII

A mixture of 1.5 parts of propanoic acid anhydride, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazine,2 parts of potassium carbonate and 130 parts of dichloromethane isstirred first for 2 hours and further after the addition of 20 parts ofwater, for one hour at room temperature. The layers are separated andthe organic phase is evaporated. The residue is crystallized from4-methyl-2-pentanone. The product is filtered off, treated withpotassium carbonate and recrystallized from 4-methyl-2-pentanone,yielding 3.6 parts (66%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(1-oxopropyl)piperazine;mp. 122.7° C.

EXAMPLE XXXIII

A mixture of 10 parts of carbon disulfide, 19.6 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,2.4 parts of sodium hydroxide, 80 parts of methanol and 100 parts ofwater is stirred for 3 hours at room temperature. Then there are added7.5 parts of dimethyl sulfate and stirring is continued for one hour atroom temperature. Water is added and the product is extracted withdichloromethane. The extract is dried, filtered and evaporated. Theresidue is triturated in 4-methyl-2-pentanone. The product is filteredoff and crystallized from ethanol, yielding 23.1 parts (100%) ofcis-methyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarbodithioate;mp. 132.9° C.

EXAMPLE XXXIV

A mixture of 1.7 parts of phenyl carbonochloridate, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-piperazine,2 parts of potassium carbonate and 130 parts of dichloromethane isstirred first for 2 hours at room temperature and further, after theaddition of 20 parts of water, for one hour at the same temperature.From the reaction mixture the organic phase is separated and evaporated.The residue is triturated in a mixture of 4-methyl-2-pentanone and2,2'-oxybispropane. The product is filtered off and crystallized from4-methyl-2-pentanone, yielding 5.3 parts (87%) of cis-phenyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxylate;mp. 159.5° C.

EXAMPLE XXXV

Following the procedure of Example XX-B and using equivalent amounts ofthe appropriate starting materials the following compounds are stillobtained:

trans-1-acetyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;

1-acetyl-4-{4-[2-(4-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;

1-acetyl-4-{4-[2-(4-bromophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;

1-acetyl-4-{4-[2-(4-fluorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;

1-acetyl-4-{4-[2-(2,6-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;

1-acetyl-4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;and

1-acetyl-4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-chloro-2-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine.

EXAMPLE XXXVI

A mixture of 174 parts of 2-bromo-1-(3-chlorophenyl)-ethanone, 81 partsof 1,2,3-propanetriol, 7.4 parts of 4-methylbenzenesulfonic acid, 94parts of 1-butanol and 528 parts of benzene is stirred and refluxed for20 hours with water-separator. The reaction mixture is poured onto adiluted sodium hydroxide solution and the layers are separated. Theaqueous phase is extracted twice with methylbenzene. The combinedorganic phases are washed twice with water, dried, filtered andevaporated, yielding 238 parts ofcis+trans-2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolane-4-methanol asa residue.

238 Parts ofcis+trans-2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolane-4-methanolare dissolved in a mixture of 144 parts of pyridine and 1135 parts oftrichloromethane and the solution is cooled to about 5° C. Then thereare added dropwise 149 parts of benzoyl chloride at a temperature below10° C. Upon completion, stirring is continued for 2 hours at roomtemperature. The reaction mixture is poured onto water and the layersare separated. The aqueous phase is extracted twice withtrichloromethane. The combined extracts are washed twice with water,dried, filtered and evaporated. The residue is stirred for a few hoursin hexane. The precipitated product is filtered off and dried at theair, yielding 128 parts ofcis+trans-[2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolan-4-ylmethyl]benzoate.

A mixture of 26 parts of 1H-imidazole and 68.5 parts of sodiummethanolate solution 30% is stirred and refluxed for 15 minutes. 90Parts of N,N-dimethylformamide are added and the methanol is distilledoff till an internal temperature of 130° C. Then there is added dropwisea solution of 102.5 parts ofcis+trans-[2-(bromomethyl)-2-(3-chlorophenyl)-1,3-dioxolan-4-ylmethyl]benzoate in 225 parts of N,N-dimethylformamide. Upon completion,stirring is continued for 3 hours at reflux. The reaction mixture iscooled, water is added and the product is extracted three times with4-methyl-2-pentanone. The combined extracts are washed twice with water,dried, filtered and evaporated, yielding 43 parts ofcis+trans-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate as a residue.

A mixture of 45 parts ofcis+trans-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate, 36 parts of sodium hydroxide solution 50%, 600 parts of1,4-dioxane and 200 parts of water is stirred and refluxed for 1 hour.The reaction mixture is cooled and poured onto water. Trichloromethaneis added and the layers are separated. The organic phase is washed withwater, dried, filtered and evaporated. The residue is converted into thehydrochloride salt in 2-propanone and 2-propanol. After stirring for 2hours in an ice-bath, the salt is filtered off and dried, yielding 14parts ofcis+trans-2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanolmonohydrochloride; mp. 198.3° C.

A mixture of 68 parts ofcis+trans-2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanoland 570 parts of pyridine is cooled to 0° C. The ice-bath is taken awayand 26.3 parts of methanesulfonyl chloride are added dropwise(exothermic reaction: temp. rises to 20° C.). Upon completion, stirringis continued for 3 hours at room temperature. The reaction mixture ispoured onto water and the product is extracted with trichloromethane.The extract is dried, filtered and evaporated. The residue is convertedinto the hydrochloride salt in 2-propanone and 2-propanol. The salt isfiltered off and crystallized from 2-propanol, yielding 32 parts of[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate monohydrochloride.

EXAMPLE XXXVII

Following the procedure of Example XXXVI and using equivalent amounts ofthe appropriate starting materials, the following methanesulfonates areprepared:

[2-(1H-imidazol-1-ylmethyl)-2-(3-methylphenyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate; and

[2-(1-H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate.

EXAMPLE XXXVIII

A mixture of 1.6 parts of 1H-1,2,4-triazole, 54 parts ofN,N-dimethylformamide and 45 parts of benzene is stirred and refluxedfor 2 hours. After cooling, 0.78 parts of sodium hydride dispersion 78%are added and the whole is stirred for 30 minutes at room temperature.Then there are added 8.9 parts ofcis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-ylmethylbenzoate and stirring is continued overnight at 150° C. The reactionmixture is cooled and poured onto water. The product is extracted threetimes with benzene. The combined extracts are washed twice with water,dried, filtered and evaporated, yielding 8.5 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate as a residue.

A mixture of 289 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]benzoate, 200 parts of sodium hydroxide solution 50%, 1500 parts of1,4-dioxane and 300 parts of water is stirred and refluxed for 2 hours.The reaction mixture is cooled and poured onto water. The product isextracted with dichloromethane. The extract is washed with water, dried,filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The firstfraction is collected and the eluent is evaporated, yielding 89 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol;mp. 138.2° C.

A mixture of 30.6 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanoland 75 parts of pyridine is stirred at room temperature and there areadded dropwise 17.2 parts of methanesulfonyl chloride. Upon completion,stirring is continued overnight at room temperature. The reactionmixture is poured onto ice-water and the product is extracted twice withdichloromethane. The combined extracts are washed twice with a dilutedhydrochloric acid solution and twice with water, dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (95:5 by volume) aseluent. The first fraction is collected and the eluent is evaporated,yielding 21 parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate; mp. 98° C.

EXAMPLE XXXIX

A mixture of 13.2 parts of 1-(4-methoxyphenyl)piperazinedihydrochloride, 5.1 parts of 1-butanal, 9 parts of sodium acetate and80 parts of methanol is hydrogenated at normal pressure and at roomtemperature with 1 part of palladium-on-charcoal catalyst. After thecalculated amount of hydrogen is taken up, the catalyst is filtered offand the filtrate is evaporated. Water is added to the residue and theproduct is precipitated. It is filtered off, washed with water andconverted into the hydrochloride salt in ethanol and 2-propanol. Underthe addition of 2,2'-oxybispropane, the salt is precipitated. It isfiltered off and crystallized from a mixture of ethanol and2,2'-oxybispropane, yielding 13.1 parts (81%) of1-butyl-4-(4-methoxyphenyl)piperazine dihydrochloride; mp. 214.2° C.

EXAMPLE XL

Following the procedure of Example XXXIX and using an equivalent amountof an appropriate aldehyde or ketone in place of the 1-butanal usedtherein, there are prepared:

1-(4-methoxyphenyl)-4-propylpiperazine dihydrochloride; mp. 214.7° C.;

1-(4-methoxyphenyl)-4-(1-methylpropyl)piperazine dihydrochloride; mp.223.5° C.;

1-(4-methoxyphenyl)-4-(2-methylpropyl)piperazine dihydrochloride; mp.220.3° C.;

1-(4-methoxyphenyl)-4-(1-methylethyl)piperazine dihydrochloride; mp.230.1° C.; and

1-(4-methoxyphenyl)-4-(phenylmethyl)piperazine dihydrochloride; mp. 234°C.

EXAMPLE XLI

A mixture of 12.5 parts of 1-butyl-4-(4-methoxyphenyl)-piperazinedihydrochloride and 150 parts of hydrobromic acid solution 48% inglacial acetic acid is stirred and refluxed overnight. The reactionmixture is evaporated and the residue is triturated in 2-propanone. Theproduct is filtered off and crystallized from water, yielding 13.1 parts(81%) of 4-(4-butyl-1-piperazinyl)phenol monohydrobromide; mp. 281.9° C.

EXAMPLE XLII

Following the procedure of Example XLI and using an equivalent amount ofan appropriate (4-methoxyphenyl)piperazine in place of the1-butyl-4-(4-methoxyphenyl)piperazine dihydrochloride used therein thereare obtained:

4-(4-propyl-1-piperzinyl)phenol sesquihydrobromide; mp. 241.8° C.;

4-[4-(1-methylpropyl)-1-piperazinyl]phenol dihydrobromide; mp. 280.4°C.;

4-[4-(2-methylpropyl)-1-piperazinyl]phenol; mp. 179.4° C.;

4-[4-(1-methylethyl)-1-piperazinyl]phenol; mp. 247.4° C.; and

4-[4-(phenylmethyl)-1-piperazinyl]phenol monohydrobromide; mp. 264.7°C.;

EXAMPLE XLIII

A mixture of 17 parts of 4-(1-piperazinyl)phenyl dihydrobromide, 7 partsof ethyl carbonochloridate, 21 parts of potassium carbonate and 250parts of 1,4-dioxane is stirred and refluxed for 48 hours. The reactionmixture is filtered, while hot and the filtrate is evaporated. The solidresidue is dissolved in a diluted hydrochloric acid solution. Thesolution is alkalized with ammonium hydroxide. The product is filteredoff and dried, yielding 3.5 parts of ethyl4-(4-hydroxyphenyl)-1-piperazinecarboxylate; mp. 168.8° C.

EXAMPLE XLIV

Following the procedure of Example XLIII and using an equivalent amountof respectively 2- and 3-(1-piperazinyl)phenol dihydrobromide in placeof the 4-(1-piperazinyl)phenol used therein, there are prepared:

ethyl 4-(2-hydroxyphenyl)-1-piperazinecarboxylate; mp. 141.8° C.; and

ethyl 4-(3-hydroxyphenyl)-1-piperazinecarboxylate; mp. 123.4° C.

EXAMPLE XLV

To a stirred solution of 80 parts of 3-(1-piperazinyl)phenoldihydrobromide in 360 parts of water and 180 parts of trichloromethaneare added portionwise 42 parts of sodium hydrogen carbonate at 10° C.Then there are added dropwise, during a 15 minutes-period, 26 parts ofacetic acid anhydride while cooling at 10° C. Upon completion, stirringis continued for 3 hours at room temperature. The precipitated productis filtered off, washed with water and crystallized from 2-propanol,yielding 37 parts (70%) of 1-acetyl-4-(3-hydroxyphenyl)piperazine; mp.186.1° C.

EXAMPLE XLVI

To a stirred mixture of 12.9 parts of 4-(1-piperazinyl)-phenoldihydrobromide, 40 parts of ethanol and 50 parts of water are added 12.6parts of sodium hydrogen carbonate. Then there are added dropwise 6.4parts of methanesulfonyl chloride at 0° C. Upon completion, stirring iscontinued overnight. The precipitated product is filtered off and takenup in water. The whole is alkalized with a sodium hydroxide solution andstirred for 30 minutes at room temperature. The mixture is filtered overhyflo and the filtrate is acidified with acetic acid. The precipitatedproduct is filtered off and dried, yielding 2.8 parts of1-(4-hydroxyphenyl)-4-(methylsulfonyl)piperazine; mp. 204.9° C.

EXAMPLE XLVII

To a stirred solution of 3.6 parts ofN-(4-hydroxyphenyl)-N-methylacetamide in 100 parts of dimethylsulfoxideare added 0.7 parts of sodium hydride dispersion 78% and stirring iscontinued till foaming has ceased. Then there are added 8.4 parts ofcis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethylmethanesulfonate and the whole is stirred for 3 hours at 100° C. Thereaction mixture is cooled and poured onto water. The product isextracted with dichloromethane. The extract is washed with a dilutedsodium hydroxide solution, dried, filtered and evaporated. The residueis converted into the ethanedioate salt in 2-propanol. The salt isfiltered off and crystallized from 2-propanol, yielding 9.2 parts ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-methylacetamideethanedioate (1:1); mp. 110° C.

EXAMPLE XLVIII

Following the procedure of Example IV and using equivalent amounts ofthe appropriate starting materials the following compounds are obtainedin free base form or in the form of an acid addition salt after treatingthe free base with an appropriate acid:

    __________________________________________________________________________     ##STR55##                                                                    Ar        R.sub.4   Base or Salt                                                                            Isomer                                                                            mp.                                         __________________________________________________________________________    2.4-Cl.sub.2C.sub.6 H.sub.3                                                           CH.sub.3    2(COOH).sub.2 . C.sub.2 H.sub.5 OH                                                      cis 136.7° C.                            2,4-Cl.sub.2C.sub.6 H.sub.3                                                           CH(CH.sub.3)CH.sub.2CH.sub.3                                                              3HCl . H.sub.2 O                                                                        cis 193.6° C.                            2,4-Cl.sub.2C.sub.6 H.sub.3                                                           CH.sub.2CH(CH.sub.3).sub.2                                                                3HCl . H.sub.2 O                                                                        cis 179.8° C.                            2,4-Cl.sub.2C.sub.6 H.sub.3                                                           CH(CH.sub.3).sub.2                                                                        3HCl . CH.sub.3                                                                         cis 192.8° C.                                                CHOHCH.sub.3                                              2,4-Cl.sub.2C.sub.6 H.sub. 3                                                          (CH.sub.2).sub.3 CH.sub.3                                                                 3HCl . H.sub.2 O                                                                        cis 178.5° C.                            2,4-Cl.sub.2C.sub.6 H.sub.3                                                           CH.sub.2CH.sub.2CH.sub.3                                                                  21/2 (COOH).sub.2                                                                       cis 171.1° C.                            2,4-Cl.sub.2C.sub.6 H.sub.3                                                           CH.sub.2C.sub.6 H.sub.5                                                                   3HCl . H.sub.2 O                                                                        cis 212.8° C.                            3-CH.sub.3C.sub.6 H.sub.4                                                             COCH.sub.3  (E)HOOCCH --  162.7° C.                                                CHCOOH                                                    2,4-Cl.sub.2C.sub.6 H.sub.3                                                           C.sub.6 H.sub.5                                                                           base      cis 209° C.                              3-ClC.sub.6 H.sub.4                                                                   COCH.sub.3  (COOH).sub.2                                                                            cis 190.9° C.                            __________________________________________________________________________

EXAMPLE IL

Following the procedure of Example IV and using equivalent amounts ofthe appropriate starting materials the following compounds are stillprepared:

cis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-2-nitrobenzenamine;mp. 148.1° C.;

cis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-N-ethylbenzenamine;mp. 143° C.; and

cis-ethyl4-{2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazinecarboxylatedihydrochloride; mp. 195.4° C.

EXAMPLE L

Following the procedure of Example III and using equivalent amounts ofthe appropriate starting materials the following compounds are prepared:

ethyl4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxylate(E)-2-butenedioate (2:1); mp. 159.9° C.;

1-acetyl-4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;mp. 171.4° C.;

cis-ethyl4-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-1-piperazinecarboxylate;mp. 119.5° C.; and

cis-1-acetyl-4-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazinedihydrobromide monohydrate; mp. 206.5° C.

EXAMPLE LI

Following the procedure of Example VII and using an equivalent amount ofan appropriate N-(hydroxyphenyl)acetamide in place of theN-(4-hydroxyphenyl)propanamide used therein, there are prepared:

cis-N-{2-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamidenitrate; mp. 183.6° C.; and

cis-N-{3-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamidenitrate; mp. 170.5° C.

EXAMPLE LII

A mixture of 2.2 parts of N-(5-hydroxy-2-nitrophenyl)-acetamide, 4.2parts ofcis-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate, 3 parts of potassium carbonate and 90 parts ofN,N-dimethylformamide is stirred and heated overnight at 120° C. Thereaction mixture is cooled and poured onto water. The product isextracted twice with dichloromethane. The combined extracts are washedtwice with a potassium carbonate sodium, dried, filtered and evaporated.The residue is taken up in 80 parts of methanol and 2 parts of a sodiummethanolate solution 30% are added. The whole is stirred and refluxedfor 1 hour. The mixture is poured onto water and the layers areseparated. The organic phase is dried, filtered and evaporated. Theresidue is converted into the hydrochloride salt in 2-propanol. The saltis filtered off and crystallized from ethanol, yielding 1.3 parts (25%)ofcis-5-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-2-nitrobenzenamine monohydrochloride; mp. 242.9° C.

EXAMPLE LIII

Following the procedure of Example LII and using equivalent amounts ofthe appropriate starting materials, the following compound are prepared:

    ______________________________________                                         ##STR56##                                                                    R.sub.4         Base or Salt form                                                                           mp.                                             ______________________________________                                        CH.sub.3        base          126.1° C.                                C.sub.2 H.sub.5 base          122.2° C.                                CH.sub.2CH.sub.2CH.sub.3                                                                      base          115.6° C.                                CH(CH.sub.3).sub.2                                                                            base          116.3° C.                                (CH.sub.2).sub.3CH.sub.3                                                                      base          111.4° C.                                CH.sub.2CH(CH.sub.3).sub.2                                                                    base          120.3° C.                                CH(CH.sub.3)CH.sub.2CH.sub.3                                                                  base          100.5° C.                                COCH.sub.3      base          176.4° C.                                SO.sub.2CH.sub.3                                                                              base 1/2H.sub.2 O                                                                           152.1° C.                                CH.sub.2C.sub.6 H.sub.5                                                                       base          107.1° C.                                C.sub.6 H.sub.5 base          134.1° C.                                ______________________________________                                    

EXAMPLE LIV

To a stirred and cooled (water-bath) mixture of 25 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,27.7 parts of potassium carbonate and 375 parts of trichloromethane areadded dropwise 5.7 parts of methyl carbonochloridate at a temperaturebetween 20° and 23° C. Upon completion, stirring is continued for 2hours. The reaction mixture is filtered over hyflo and the filtrate isevaporated. The residue is converted into the hydrochloride salt in4-methyl-2-pentanone, a small amount of methanol and 2-propanol. Thesalt is filtered off and dried, yielding 23 parts (74.15%) of cis-methyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxylatedihydrochloride; mp. 192.9° C.

EXAMPLE LV

Following the procedure of Example LIV and using equivalent amounts ofthe appropriate starting materials the following compounds are prepared:

cis-methyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxylate;mp. 134.7° C.;

cis-ethyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}1-piperazinecarboxylatedihydrochloride; mp. 170.4° C.;

cis-ethyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxylatedihydrochloride hemihydrate; mp. 178° C.; and

cis-phenyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxylate;mp. 112.4° C.

EXAMPLE LVI

A mixture of 1.56 parts of propanoic acid anhydride, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,2 parts of potassium carbonate and 130 parts of dichloromethane isstirred for 2 hours at 10° C. Water is added and the layers areseparated. The organic phase is washed with water, dried, filtered andevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and methanol (97:3 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The residue is converted into the hydrochloride salt in2,2'-oxybispropane and 2-propanol. The salt is filtered off andcrystallized from a mixture of 2-propanol and 2,2'-oxybispropane,yielding 1.2 parts ofcis-1{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(1-oxopropyl)piperazinedihydrochloride; mp. 180.9° C.

EXAMPLE LVII

Following the procedure of Example LVI and using an equivalent amount ofbutanoic acid anhydride in place of the propanoic acid anhydride usedtherein there is prepared:

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(1-oxobutyl)piperazinedihydrochloride; mp. 177.7° C.

EXAMPLE LVIII

A mixture of 1.34 parts of ethyl-2-chloroacetate, 5 parts ofcis-1-{4-[2(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,2.75 parts of potassium carbonate and 45 parts of N,N-dimethylformamideis stirred and heated for 1 hour at 60° C. The reaction mixture ispoured onto icewater. The product is extracted with dichloromethane. Theextract is washed with water, dried, filtered and evaporated. The oilyresidue is purified by column-chromatography over silica gel using amixture of methylbenzene and ethanol (90:10 by volume) as eluent. Thepure fractions are collected and the eluent is evaporated. The oilyresidue is crystallized from 4-methyl-2-pentanone. The product isfiltered off and dried, yielding 2 parts of cis ethyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-phenyl}-1-piperazineacetate;mp. 130.7° C.

EXAMPLE LIX

A mixture of 1 part of 2-chloroacetamide, 5 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,2.76 parts of potassium carbonate and 50 parts of dimethylsulfoxide isstirred for 60 hours at room temperature. The reaction mixture is pouredonto water and the product is extracted with dichloromethane. Theextract is washed with water, dried, filtered and evaporated. The solidresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and methanol (95:5 by volume) as eluent. Thepure fractions are collected and the eluent is evaporated, yielding 1.5parts ofcis-4-{4-[2(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazineacetamide;mp. 150.2° C.

EXAMPLE LX

To a stirred solution of 5 parts of ethanamine in 55 parts of1,2-ethanediol are added 4.5 parts of cis-ethyl4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy}phenyl}-1-piperazineacetateand the whole is stirred first for 5 hours at 40° C. and further for 48hours at room temperature. The reaction mixture is poured onto water andthe product is extracted with dichloromethane. The extact is dried,filtered and evaporated. The oily residue is crystallized from a mixtureof ethyl acetate and 2,2'-oxybispropane. The product is filtered off anddried, yielding 3 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-ethyl-1-piperazine-acetamide;mp. 117.2° C.

EXAMPLE LXI

Following the procedure of Example LX and using an equivalent amount ofmethanamine in place of the ethanamine used therein there is prepared:

cis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-methyl-1-piperazineacetamidetrihydrochloride, monohydrate; mp. 212.2° C.

EXAMPLE LXII

A mixture of 20.7 parts ofcis-N-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-N-methylacetamideethanedioate (1:1), 15 parts of potassium hydroxide and 160 parts of2-propanol is stirred and refluxed overnight. The reaction mixture iscooled and poured onto water. The product is extracted withdichloromethane. The extract is washed with water, dried, filtered andevaporated. The residue is converted into the ethanedioate salt inethanol. The salt is filtered off. The free base is liberated in theconventional manner and crystallized from 1,1'-oxybisethane, yielding 9parts (57%) ofcis-4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-N-methylbenzenamine;mp. 118.4° C.

EXAMPLE LXIII

A mixture of 53.7 parts ofcis-1-acetyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl-methoxy]phenyl}piperazine,4.9 parts of sodium hydroxide and 800 parts of 1-butanol is stirred andrefluxed overnight. The reaction mixture is cooled and poured ontowater. The product is extracted with benzene. The extract is washedtwice with water, dried, filtered and evaporated. The residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume), saturated with ammonia,as eluent. The pure fractions are collected and the eluent isevaporated. The residue is crystallized from 2,2'-oxybispropane. Theproduct is filtered off and dried, yielding 11.7 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;mp. 130.6° C.

EXAMPLE LXIV

A mixture of 60 parts of formic acid and 6 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazineis stirred and refluxed overnight. The reaction mixture is evaporatedand the residue is dissolved in water. The solution is alkalized withammonium hydroxide and the product is extracted twice withdichloromethane. The combined extracts are washed twice with water,dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane, hexane and methanol (45:45:10 by volume) as eluent.The pure fractions are collected and the eluent is evaporated. Theresidue is crystallized from 4-methyl-2-pentanone. The product isfiltered off and dried, yielding 2.5 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxaldehyde;mp. 137.3° C.

EXAMPLE LXV

A mixture of 2.3 parts of benzoyl chloride, 7.35 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,3 parts of potassium carbonate and 130 parts of dichloromethane isstirred for 2 hours at room temperature. The reaction mixture is washedwith water, dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 2,2'-oxybispropane. The product is filtered off anddried, yielding 1.8 parts ofcis-1-benzoyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine;mp. 140.3° C.

EXAMPLE LXVI

A mixture of 1.3 parts of methanesulfonyl chloride, 4.9 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,3 parts of potassium carbonate and 150 parts of trichloromethane isstirred for 3 hours at room temperature. Then there are added 100 partsof water and stirring is continued for 1 hour at room temperature. Theorganic phase is separated, dried, filtered and evaporated. The residueis triturated in a mixture of 4-methyl-2-pentanone and five drops ofwater. Upon the addition of 2,2'-oxybispropane, the product isprecipitated. It is filtered off and crystallized from4-methyl-2-pentanone, yielding 5 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(methylsulfonyl)piperazinemonohydrate; mp. 113° C.

EXAMPLE LXVII

Following the procedure of Example LXVI and using equivalent amounts ofthe appropriate starting materials there are prepared:

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(phenylmethylsulfonyl)piperazine;mp. 188.2° C.; and

cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(phenylmethylsulfonyl)piperazinemonohydrate; mp. 135.1° C.

EXAMPLE LXVIII

During 1 hour, gaseous oxirane is bubbled through a stirred mixture of 5parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazineand 80 parts of methanol at reflux temperature. The reaction mixture isevaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichlormethane and methanol (95:5 by volume) aseluent. The pure fractions are collected and the eluent is evaporated.The oily residue is crystallized from a mixture of benzene andpetroleumether. The product is filtered off and dried, yielding 2 partsofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazineethanol;mp. 146.4° C.

A mixture of 5.3 parts ofcis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazineethanol,50 parts of dimethylsulfoxide and 45 parts of benzene is stirred tillall solid enters solution. Then there are added 0.622 parts of sodiumhydride dispersion 76% and stirring at room temperature is continuedtill gas-evolution has ceased. 2.2 Parts of bromoethane are added andthe whole is stirred overnight at room temperature. Another 2 parts ofbromoethane are added in two separate portions, each time with a 2hours-time interval. The reaction mixture is poured onto ice-water andthe product is extracted with dichloromethane. The extract is washedwith water, dried, filtered and evaporated. The oily residue is purifiedby column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions are collected and the eluent is evaporated. The oily residueis crystallized from 4-methyl-2pentanone. The product is filtered offand dried, yielding 2.7 parts ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}4-(2-ethoxyethyl)piperazine;mp. 140°-145.4° C.

EXAMPLE LXIX

A mixture of 5 parts ofcis-1-acetyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine,1 part of lithium aluminium hydride and 90 parts of tetrahydrofuran isstirred for one week at room temperature. The reaction mixture isdecomposed by the successive additions of 1 part of water, 1.50 parts ofa sodium hydroxide solution 50% and 3 parts of water. The precipitate isfiltered off and the filtrate is evaporated. The residue is convertedinto the ethanedioate salt in ethanol. The salt is filtered off anddried, yielding 3.7 parts (56%) ofcis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-ethylpiperazineethanedioate; mp. 169.7° C.

EXAMPLE LXX

A mixture of 60 parts ofcis-1-acetyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazineand 400 parts of 4-methyl-2-pentanone is heated to reflux and treatedwith activated charcoal. The latter is filtered off and the filtrate iscooled to about 30° C. Then there are added slowly 29 parts of2-propanol, saturated with gaseous hydrogen chloride and upon stirring,the formed hydrochloride salt is allowed to crystallize (3 hours). It isfiltered off and recrystallized twice from 2-propanol, yielding 38 partsofcis-1-acetyl-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol)-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazinedihydrochloride; mp. 219.3° C.

EXAMPLE LXXI

Following the procedure of Example XXXVI and using equivalent amounts ofthe appropriate starting materials the following methanesulfonates arestill prepared:

[2-(4-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(4-bromophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(4-fluorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(2,6-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate;

[2-(2-(1H-imidazol-1-ylmethyl)-2-(4-methylphenyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate; and

[2-(2-(1H-imidazol-1-ylmethyl)-2-(4-chloro-2-methylphenyl)-1,3-dioxolan-4-ylmethyl]methanesulfonate.

EXAMPLE LXXII

Following the procedure of Example IV and using equivalent amounts ofthe appropriate starting materials, the following compounds of formula Iare still prepared:

4-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-N-ethylbenzenamine;

4-[2-(4-bromophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-N-ethylbenzenamine;

N-ethyl-4-[2-(1H-imidazol-1-ylmethyl)-2-(3-methylphenyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;

N-ethyl-4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]benzenamine;

4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]-N-ethylbenzenamine;

N-{4[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamide.

N-{4-[2-(4-bromophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}benzamide

ethyl{4-[2-(1H-imidazol-1-ylmethyl)-2-(3-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}carbamate;

N-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-fluorobenzamide;

N-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamide;

1-{2-(3-chlorophenyl)-4-[4-(1-pyrrolidinyl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(4-bromophenyl)-4-[4-(1-piperidinyl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(3-methylphenyl)-4-[4-(1-pyrrolidinyl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(4-methoxyphenyl)-4-[4-(1-piperidinyl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-imidazole;

1-{2-(2,4-dichlorophenyl)-4-[4-(1-pyrrolidinyl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

1-{2-(2,4-dichlorophenyl)-4-[4-(1-piperidinyl)phenoxymethyl]-1,3-dioxolan-2-ylmethyl}-1H-1,2,4-triazole;

4-{4-[2-(3-chlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}morpholine;

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(3-methylphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}morpholine;

4-{4-[2-(1H-imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-ylmethoxy]phenyl}morpholine;and

4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}morpholine.

We claim:
 1. A chemical compound selected from the group consisting ofan azole derivative having the formula: ##STR57## and thepharmaceutically acceptable acid addition salts and stereochemicaloptical isomeric forms thereof, wherein:Q is N; Ar is a member selectedfrom the group consisting of phenyl and substituted phenyl, saidsubstituted phenyl being phenyl having from 1 to 3 substituentsindependently selected from the group consisting of halo, lower alkyland lower alkyloxy; the radical A is a member selected from the groupconsisting of:(a) an isothiocyanato group --N═C═S; (b) an amino radicalof the formula ##STR58## wherein R₁ and R₂ are each independentlyselected from the group consisting of hydrogen and lower alkyl; (c) aradical of the formula ##STR59## wherein X is selected from the groupconsisting of O and S, Y is selected from the group consisting of O andNH, m is the integer 0 or 1, and R₃ is selected from the groupconsisting of hydrogen, lower alkyl, mono- and dihalo(lower alkyl),phenyl and substituted phenyl, said substituted phenyl having from 1 to2 substituents independently selected from the group consisting of halo,lower alkyl and lower alkyloxy, provided that:(i) when said X is S, thensaid Y is NH and said m is 1, and (ii) when said Y is O and said m is 1,then said R₃ is other than hydrogen; and R is a member selected from thegroup consisting of hydrogen and nitro, provided that when said R isnitro, then said A is amino.
 2. A composition for combatting amicroorganism selected from the group consisting of fungus and bacteriumcomprising an inert carrier material and as an active ingredient aneffective amount of a compound selected from the group consisting of anazole derivative having the formula: ##STR60## and the pharmaceuticallyacceptable acid addition salts and stereochemical optical isomeric formsthereof, wherein:Q is N; Ar is a member selected from the groupconsisting of phenyl and substituted phenyl, said substituted phenylbeing phenyl having from 1 to 3 substituents independently selected fromthe group consisting of halo, lower alkyl and lower alkyloxy; theradical A is a member selected from the group consisting of(a) anisothiocyanato group --N═C═S; (b) an amino radical of the formula##STR61## wherein R₁ and R₂ are each independently selected from thegroup consisting of hydrogen and lower alkyl; (c) a radical of theformula ##STR62## wherein X is selected from the group consisting of Oand S, Y is selected from the group consisting of O and NH, m is theinteger 0 or 1, and R₃ is selected from the group consisting ofhydrogen, lower alkyl, mono- and dihalo(lower alkyl), phenyl andsubstituted phenyl, said substituted phenyl having from 1 to 2substituents independently selected from the group consisting of halo,lower alkyl and lower alkyloxy, provided that:(i) when said X is S, thensaid Y is NH and said m is 1, and (ii) when said Y is O and said m is 1,then said R₃ is other than hydrogen; and R is a member selected from thegroup consisting of hydrogen and nitro, provided that when said R isnitro, then said A is amino.
 3. A chemical compound selected from thegroup consisting ofN-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}acetamideand the pharmaceutically acceptable acid addition salts andstereochemical optical isomeric forms thereof.